A major announcement: There’s now evidence that an important factor in the cause of PSP are variants in two “regulatory genes” called PLEKHM1 and KANSL1, both of which are very near the MAPT (tau) gene on chromosome 17. 

Regulatory genes are not encoded into protein.  Rather, they affect the rate at which other genes are transcribed into protein, kind of like business executives or military officers directing the activities of others.  Such proteins are called “transcription factors.” The project identified the gene being regulated in this case as SP1, which encodes the protein called Sp1 (note the lowercase p; the fewer abbreviations in science, the better, I always say). SP1 is located on chromosome 12 and works in tandem with a group of other genes to regulate many cellular processes. 

As a comparator, the researchers used samples from people with Alzheimer’s disease, finding that it involved a different set of regulatory genes that did not interact with SP1.  This result could allow drugs that regulate the Sp1 protein or gene-directed therapy for the PLEKHM1 or KANSL1 genes to be developed as treatment or prevention for PSP. The new finding’s significance is underscored by its publication in Science, one of a small handful of top general scientific journals. 

The research was a collaboration between the highly productive neurodegenerative genetics groups at UCLA and UCSF, with Drs. Daniel Geschwind and Martin Kampmann, respectively, as senior members.  The first author was Yonatan Cooper, an MD/PhD student at UCLA.  In response to my email, Yonatan commented, “A key challenge in modern medicine has been interpreting genetic risk factors [for diseases of complex causation] and translating them to understand disease mechanisms. This is especially true for the 17q tau locus, which is the major genetic risk factor for PSP.  The approach that we used was crucial to allowing us to identify these new genes in that region.” 

The “approach that we used” in Yonatan’s quote is called a “massively parallel reporter assay” (MRPA).  It assesses thousands of single-nucleotide DNA variants for their ability to regulate other genes’ protein expression levels.  For this study, the researchers chose the region close to the two variants in or near the MAPT gene found in 2011 by the PSP Genetics Consortium and funded by CurePSP.  That region comprises hundreds of genes, any of which could be actual source(s) of the PSP risk in that region of the genome.

That 2011 study used “single-nucleotide polymorphisms (SNPs)” in DNA from autopsy-confirmed PSP brain tissue and control subjects.  Even now, 11 years later it remains the most informative single study on the genetics of PSP.  (Disclosure: I was a minor co-author.)  It identified a handful of regions across the genome where a marker differs between the two groups, implying that a gene near each marker contributes to the cause of PSP.  Two of those markers were in or near MAPT.  But that technique can’t positively incriminate which of the hundreds of genes in that region of chromosome 17 actually cause(s) the disease.  The current study did that by testing all of the thousands of variants in those genes for their ability to alter protein production in a way that could help cause PSP. 

One next step is to look for drugs or other treatments to counter the effect of these two regulatory abnormalities on the function of the SP1 protein and/or a protein with which it interacts.  Another next step is to use the same technique to look for other regulatory genes near the other PSP-related markers identified in the 2011 SNP study and more recently and to look for drug targets in the protein products of the genes they regulate.

I don’t know about you, but I’m nerdy enough to be very excited about this!